Parkinson's disease (PD) is a debilitating neurodegenerative disorder that causes severe motor impairments. Progressive degeneration of nigrostriatal dopamine neurons underlies these motor symptoms and there is currently no way to stop or slow this neuronal loss. Abnormal dopamine metabolism has been proposed to underlie the degeneration of these neurons. However, all dopamine neurons are not affected to the same extent in PD. In fact, while there is severe loss of midbrain nigrostriatal dopamine neurons, the hypothalamic tuberoinfundibular dopamine neurons remain intact. Our preliminary data demonstrates that a similar pattern of susceptibility in these dopamine neuronal populations when they are exposed to complex I inhibition in a mouse model of PD. Furthermore, we have ruled out several extrinsic factors previously hypothesized to underlie this differential susceptibility. We have also demonstrated that the nigrostriatal and tuberoinfundibular dopamine neurons have a similar initial response to complex I inhibition but that only tuberoinfundibular dopamine neurons are able to recover. The timeline of this recovery has been characterized and is very rapid. Our preliminary data also suggests that the protein parkin may be involved in this differential susceptibility. Constitutive parkin mRNA levels are higher in the cell body regions of tuberoinfundibular dopamine neurons when compared to cell body regions of nigrostriatal dopamine neurons. Furthermore, at the critical time point when tuberoinfundibular neurons show recovery in response to complex I inhibition, parkin mRNA levels also dramatically increase. Parkin is an E3 ligase that tags misfolded and abnormal proteins for degradation and plays a protective role in several models of neurotoxicity including mitochondrial dysfunction, oxidative damage, synuclein toxicity and proteasome inhibition. The proposed experiments will determine whether higher levels of parkin in the tuberoinfundibular dopamine neurons protect them from complex I inhibition. This will be determined by decreasing the expression of parkin mRNA and protein in tuberoinfundibular dopamine neurons and determining whether they become susceptible to complex I inhibition. Furthermore, the proposed studies will determine whether increasing parkin expression in the nigrostriatal dopamine neurons will protect them from complex I inhibitor toxicity. The proposed experiments will enhance our understanding of differential susceptibility of dopaminergic neurons in response to complex I inhibition. The results may be further translated into neuroprotective strategies that can prevent the ongoing degeneration of dopamine neurons in PD. [unreadable] [unreadable]